Jason Tedrow

An Efficient, Regioselective Amination of 3,5-Disubstituted Pyridine N-Oxides Using Saccharin as an Ammonium Surrogate

A process for the regioselective amination of unsymmetrical 3,5-substituted pyridine N-oxides has been developed utilizing cheap, readily available saccharin as an ammonium surrogate. High conversions of the corresponding saccharin adducts have been achieved under mild reaction conditions. In situ deprotection under acidic conditions allows for a one-pot process to substituted aminopyridines. High regioselectivities were obtained from a variety of 3,5-disubstituted pyridine N-oxides.

Highly Regioselective Halogenation of Pyridine N-Oxide: Practical Access to 2-Halo-Substituted Pyridines

A highly efficient and regioselective halogenation reaction of unsymmetrical pyridine N-oxide under mild conditions is described. The methodology provides a practical access to various 2-halo-substituted pyridines, which are pharmaceutically important intermediates.

Direct reductive amination of aldehyde bisulfite adducts induced by 2-picoline borane: application to the synthesis of a DPP-IV inhibitor.

Aldehyde-bisulfite adducts dervied from unstable parent aldehydes were reductively alkylated in a direct fashion with a variety of amines. This approach features the use of 2-picoline borane as the reducing agent and a protic solvent for the reaction media and has been successfully applied to the synthesis of a DPP-IV inhibitor and a variety of other amines.

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.

Separation and quantitation of eight isomers in a molecule with three stereogenic centers by normal phase liquid chromatography

A normal phase liquid chromatography method was developed for the separation and detection of eight stereoisomers of the key intermediate, CORE + OMe, having three chiral centers. The stereochemistry of this intermediate dictates the stereochemistry of the active pharmaceutical ingredient generated by an additional six synthetic steps. Multiple columns and mobile phases were screened during the development based on a platform approach. The use of dichloromethane as mobile phase additive and adjustment of flow rate and column temperature contributed in achieving resolution of these eight stereoisomers. The separation and detection of these stereoisomers was achieved using a Chiralcel OD-H, 4.6 × 250 mm, 5 μm dp column with heptane: ethanol: dichloromethane in a ratio of 95:3:2 (v:v:v) as mobile phase at a flow rate of 0.7 mL/min. UV detection was carried out at 245 nm and the column temperature was maintained at 15 °C. The analytical method was phase appropriately validated. The limit of detection and limit of quantification were found to be 0.035 and 0.07 μg, respectively. The newly developed method has been implemented for routine utilization to monitor the chiral control during process development and used as the quality control method for chiral purity of the desired compound.

Isolation and structure elucidation of unexpected in‐process impurities during tetrazole ring formation of an investigational drug substance

During the formation of a tetrazole ring on an investigational drug, two in‐process impurities were detected and analyzed by LC–MS, which suggested that both impurities were drug‐related with the same mass‐to‐charge ratio. To understand and control their formation, both impurities were isolated from the mother liquor of the reaction using a multi‐step isolation procedure to obtain a sufficient amount for high‐resolution mass spectrometry (HRMS) and NMR structural analysis. HRMS suggested a protonated mass of 577.32 Da for both impurities; however, MS fragmentation patterns provided limited information on their structures. NMR analysis indicated the presence on an additional NH functional group in both isolates with similar spatial and bond correlations to one of the dimethylcarbamoyl moieties and the corresponding aromatic ring. A phenyldimethylcarbamoylamino moiety was supported by the NMR and HRMS data and could be explained based on the ‘Schmidt‐like’ reaction mechanism, which was an unexpected reaction pathway. Because the reaction conditions were fixed because of safety concerns, the crystallization protocol was redesigned to reduce the levels of these impurities significantly. Copyright